Aging Modulates Susceptibility to Mouse Liver Mallory-Denk Body Formation
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- Shinichiro Hanada
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Masaru Harada
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Mitsuhiko Abe
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Jun Akiba
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Masahiro Sakata
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Raymond Kwan
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Eitaro Taniguchi
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Hironori Koga
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Eisuke Nagata
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Takato Ueno
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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- Michio Sata
- Division of Gastroenterology, Department of Medicine (SH,MA,MS,ET,TK,HK,TU,MS)
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説明
<jats:p> Mallory-Denk bodies (MDBs) are hepatocyte cytoplasmic inclusions found in several liver diseases and consist primarily of the cytoskeletal proteins, keratins 8 and 18 (K8/K18). Recent evidence indicates that the extent of stress-induced protein misfolding, a K8>K18 overexpression state, and transglutaminase-2 activation promote MDB formation. In addition, the genetic background and gender play an important role in mouse MDB formation, but the effect of aging on this process is unknown. Given that oxidative stress increases with aging, the authors hypothesized that aging predisposes to MDB formation. They used an established mouse MDB model—namely, feeding non-transgenic male FVB/N mice (1, 3, and 8 months old) with 3,5 diethoxycarbonyl-1,4-dihydrocollidine for 2 months. MDB formation was assessed using immunofluorescence staining and biochemically by demonstrating keratin and ubiquitin-containing crosslinks generated by transglutaminase-2. Immunofluorescence staining showed that old mice had a significant increase in MDB formation compared with young mice. MDB formation paralleled the generation of high molecular weight ubiquitinated keratin-containing complexes and induction of p62. Old mouse livers had increased oxidative stress. In addition, 20S proteasome activity and autophagy were decreased, and endoplasmic reticulum stress was increased in older livers. Therefore, aging predisposes to experimental MDB formation, possibly by decreased activity of protein degradation machinery. </jats:p>
収録刊行物
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- Journal of Histochemistry & Cytochemistry
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Journal of Histochemistry & Cytochemistry 60 (6), 475-483, 2012-04-03
SAGE Publications